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Related Announcements

PAR-21-237 - NINDS Efficacy Clinical Trials (UG3/UH3 Clinical Trial Required)

Issued by

National Institute of Neurological Disorders and Stroke (NINDS)

Purpose

Purpose

This Notice of Special Interest is to advise the research community of NINDS interest in clinical trials to study epidural stimulation in spinal cord injury that meet the requirements of PAR-21-237 NINDS Efficacy Clinical Trials (UG3/UH3 Clinical Trial Required) Funding Opportunity Announcement.

Background

The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease for all people. Spinal Cord Injury (SCI) can occur following an acute or long-term insult to the spinal cord, resulting in devastating neurological loss and concomitant systemic dysfunction with no current ameliorative treatment or cure. The most recent estimate of the incidence of traumatic SCI in the United States indicates an additional 18,000 new acute SCI cases each year, with an estimated prevalence of 300,000 individuals in the US currently living with SCI¹.

Although regeneration and repair of the injured spinal cord is not currently possible, since 2011 clinical studies of electrical stimulation of the spinal cord (spinal cord epidural stimulation, scES) have provided proof of principle that some recovery of motor function is possible even after the most severe injury. Since 2018 additional research has suggested that scES can also result in restoration of essential autonomic functions. Preclinical research has clarified some of the neurological mechanisms involved, while exploratory and mechanistic clinical trials in small patient numbers (in the range of 1-10 participants) report that scES can improve health and quality of life for individuals with chronic SCI through the restoration of a range of functional outcomes including improved motor function, bowel and bladder control, and hemodynamic regulation.

In February 2019 the NIH hosted the conference SCI 2020: Launching a Decade for Disruption in Spinal Cord Injury Research², proceedings from this meeting were published in April 2021³. Neuromodulation, including scES, to improve neurological function, was one of the top scientific domains identified as a priority by persons with lived experience with SCI and the research community. Discussion points included recommendations that neuromodulation therapies deliver outcomes that enable everyday living and preserve health and well-being for the future and could include approaches targeting respiratory, urinary, musculoskeletal, and cardiovascular systems. At more recent meetings of the SCI research and public stakeholder communities, investigators have continued to report results from small exploratory clinical trials and have built the body of evidence to the point where community members have expressed confidence that the field is ready for an efficacy study, described in the medical device field as a Pivotal study, of the use of scES for recovery after SCI. A medical device Pivotal study is a definitive study in which evidence is gathered to support the safety and effectiveness evaluation of the medical device for its intended use. Evidence from one or more Pivotal clinical studies generally serves as the primary basis for the determination of reasonable assurance of safety and effectiveness of the medical device of a Pre-Market Approval application (PMA) from the FDA.

The FDA provides guidance for such studies, as described in the Objectives, below. In all cases the investigators need to work closely with the FDA to ensure the designed study does meet the requirements for a Pivotal study.

Investigators studying epidural stimulation where the research is not ready for a well-designed Pivotal study should reach out to the contact PO for advice on other appropriate funding opportunities such as Pilot/Early Feasibility or mechanistic clinical trials.

Objectives

1. To make the scientific community aware of NINDS interest in qualifying applications of epidural stimulation to PAR-21-237: NINDS Efficacy Clinical Trials (UG3/UH3 Clinical Trial Required) (nih.gov) This FOA uses a phased UG3/UH3 award mechanism. Only projects that provide satisfactory progress in the UG3 phase may move to the UH3 phase. The objective of this NOSI is to encourage investigators with epidural stimulation clinical trials that are ready for this next step to submit to PAR-21-237 for the 02/09/2023 deadline.
2. To highlight for the scientific community some key features to be considered for applications to PAR-21-237.

• PAR-21-237 supports Phase 3 or Phase 4 clinical trials/Pivotal device trials conducted to provide a definitive answer regarding the safety and efficacy of an intervention or to compare the effectiveness of two or more interventions. The proposed research must address a scientifically important question, provide valuable information to the existing knowledge base, and have public health relevance. The trial design should ensure that high quality, complete data regarding the primary outcome will be collected in the most efficient manner in terms of time, resources, and burden to subjects. Secondary outcomes should be included only when they are anticipated to provide important supportive or explanatory data. The necessity of each secondary endpoint must be justified in light of cost and burden. Pragmatic trials requiring minimal data collection and low cost per subject are encouraged. This FOA also may be used for the submission of an adaptive trial utilizing a seamless Phase 2/3 transition, equivalent for a medical device to a Traditional Feasibility (safety-efficacy)/Pivotal study design.

• The scientific premise for the trial should be based on preclinical and/or clinical data from rigorously performed studies (see https://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-103.html). If previous research does not meet the rigor criteria outlined to an acceptable degree, applicants should address how the current study design addresses the deficiencies. NINDS, as part of NIH, strives for rigor and transparency in all research it funds. For this reason, NINDS explicitly emphasizes the NIH application instructions related to rigor and transparency (https://grants.nih.gov/policy/reproducibility/guidance.htm) and provides additional resources for the scientific community (https://www.ninds.nih.gov/Funding/grant_policy).
• FDA approval of the protocol to be used for the proposed Pivotal trial is an important part of applications to PAR-21-237. Applicants should review sections 4.5 and 7 of the FOA for specifics. To meet these requirements applicants are encouraged to begin discussions with the FDA as early as possible. Reports of such Pre-submission and Q-submission meetings can be included in the application as evidence of coordination with the FDA. FDA resources that may be helpful are included here as information for the applicants:
  • Requests for Feedback and Meetings for Medical Device Submissions: The Q-Submission Program | FDA
  • PMA Guidance Documents | FDA
  • Factors to Consider When Making Benefit-Risk Determinations in Medical Device Premarket Approval and De Novo Classifications (fda.gov)
• It is acknowledged that costs for a well-designed Pivotal clinical trial in this space may exceed the $500,000 per year direct cost threshold. As described in PAR-21-237, applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/ Research Contact at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide.
• Applicants are strongly encouraged to establish relationships with patient groups and solicit their input on recruitment, the clinical meaningfulness of the question under study, the relevance of the proposed clinical outcomes, and approaches to minimizing the burden on study subjects.
• Applications will need to comply with the new NIH Data Management and Sharing Policy, effective January 25, 2023 Research Covered Under the Data Management & Sharing Policy | Data Sharing (nih.gov). It is anticipated that PAR-21-237 will be updated with details of the requirements, applicants can reach out to the contact PO and request to be notified when this FOA is updated. Investigators can also refer to the FAQ page, https://sharing.nih.gov/faq.

¹ National Spinal Cord Injury Statistical Center, Traumatic Spinal Cord Injury Facts and Figures at a Glance. Birmingham, AL: University of Alabama at Birmingham, 2022.

²SCI 2020: Launching a Decade for Disruption in Spinal Cord Injury Research | National Institute of Neurological Disorders and Stroke (nih.gov)

³Morse, L et al., Journal of Neurotrauma volume 38, Number 9, pp 1251-1266. DOI: 10.1089/neu.2020.7174

Application and Submission Information

This notice applies to the February 9 ,2023 receipt date and subsequent due dates through October 10, 2023.

Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcement through the expiration date of this notice.

• PAR-21-237 - NINDS Efficacy Clinical Trials (UG3/UH3 Clinical Trial Required)

All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:

• For funding consideration, applicants must include “NOT-NS-23-038” (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.

Inquiries

Linda Bambrick, PhD
NINDS
301-496-1447
linda.bambrick@nih.gov